外位点介导的二聚体颗粒酶A靶向GSDMB在淋巴细胞焦亡性杀伤中的作用，这一成果由中国科学院生物物理研究所丁璟珒团队经过不懈努力而取得。该项研究成果发表在2026年1月26日出版的《免疫学》上。

该课题组发现人类GZMA通过特异性、高亲和力结合GSDMB-C结构域靶向GSDMB。这种结合需要GZMA的二聚化，这是人类颗粒酶的独特特性。GZMA-GSDMB-C配合物的晶体结构显示出2:2的化学计量，在GZMA的两个对称二聚体界面上各有一个外源点。该外源位点参与GSDMB-C结构域的一个双环组织位点，在GSDMB的Lys244位点进行功能性切割。小鼠GZMA （mGZMA）采用类似的二聚体结构，但其外源位点与GSDMB的结合效率较低。外源位点的突变使mGZMA能够有效地切割和激活GSDMB。他们的研究揭示了一种以淋巴细胞衍生的颗粒酶为主题的底物靶向机制，以杀死靶细胞。

据悉，在细胞免疫中，细胞毒性淋巴细胞利用颗粒酶A （GZMA）裂解并激活成孔蛋白gasdermin B (GSDMB)，以热噬杀死靶细胞。GZMA如何识别和切割GSDMB是未知的。

附：英文原文

Title: Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing

Author: Xiu Zhong, Ya Su, Zhiwei Zhou, Yuqiu Sun, Yanjie Hou, Feng Shao, Jingjin Ding

Issue&Volume: 2026-01-26

Abstract: In cellular immunity, cytotoxic lymphocytes employ granzyme A (GZMA) to cleave and activate the pore-forming protein gasdermin B (GSDMB) for the pyroptotic killing of target cells. How GZMA recognizes and cleaves GSDMB is unknown. Here, we show that human GZMA targets GSDMB via specific, high-affinity binding to its autoinhibitory GSDMB-C domain. This binding requires the dimerization of GZMA, a unique property among human granzymes. A crystal structure of the GZMA-GSDMB-C complex shows a 2:2 stoichiometry, featuring an exosite at each of the two symmetric dimer interfaces in GZMA. The exosite engages a two-loop-organized site in the GSDMB-C domain, rendering a functional cleavage at Lys244 in GSDMB. Mouse GZMA (mGZMA) adopts a similar dimer structure, but its exosite is less efficient in engaging GSDMB. Mutation of the exosite enabled mGZMA to efficiently cleave and activate GSDMB. Our study reveals a substrate-targeting mechanism used by lymphocyte-derived granzymes to kill target cells.

DOI: 10.1016/j.immuni.2025.12.009

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00565-5